U.S. Pat. No. 6,071,497, issued Jun. 6, 2000 to Steiner et al., describes methods to manufacture microparticles of a diketopiperazine that involves a precipitation of the microparticles. The method described in U.S. Pat. No. 6,071,497, however, is a process in which a drug is incorporated in the microparticles as they form. Alternatively, U.S. Pat. No. 6,444,226 discloses a method for making a formulation using preformed diketopiperazine microparticles by forming a complex of the microparticles with an active agent. Such microparticle suspensions can be further processed to produce dry powder that can be administered to a patient by inhalation for therapeutic purposes. In all of the described methods, precipitation reactions involving diketopiperizine are extremely fast, with a reaction half-time in the order of 0.5 second, and the precipitated suspension is a non-Newtonian fluid.
A precipitation process is typically used to produce small particles, as the crystal formation in the precipitation takes place very rapidly. Conditions used during the precipitation process define the particle size and the structure of the particles. The process involves bringing dissolved solid mixtures to supersaturation while mixing. The mixing rate and level of supersaturation play an important role in particle size formation. Prior art mixing apparatus includes impinging jet mixers, high pressure homogenizers and static mixing followed by spray drying. None of these devices can be used in a continuous process, if the precipitation process is extremely fast and the resulting suspension is a non-Newtonian fluid. The non-Newtonian nature of the fluid causes precipitated particles to stick to the wall of the precipitation device if velocity gradients are small in the exit stream. Thus, clogging of the mixing apparatus can occur.
Accordingly, there is a need for improved reactors, reactor systems and methods for producing particles in a continuous precipitation process.